daraxonrasib (RMC-6236) / Revolution Medicines - LARVOL DELTA

Dr Vonderheide on Responses With RAS(ON) Inhibition in Preclinical Pancreatic Cancer Models (OncLive) - "RAS(ON) multi-selective inhibitors, including agents such as RMC-6236 and RMC-7977, target the active, GTP-bound state of both mutant and wild-type RAS isoforms and have demonstrated potent antitumor activity in PDAC murine models....The findings revealed 3 primary observations, according to Vonderheide. First, treatment with KRAS(ON) multi-selective inhibitors resulted in marked tumor regression, with effects more profound than previously observed in laboratory models. Second, in mice lacking T cells, the antitumor efficacy of KRAS inhibition was significantly diminished, indicating that T cells contribute meaningfully to therapeutic response. Third, the addition of immune-based therapies, including checkpoint blockade, enhanced the depth and durability of tumor regressions. In some cases, mice achieved complete and sustained remissions even after discontinuation of the KRAS inhibitor, suggesting an immunologic memory response."

Preclinical • Pancreatic Ductal Adenocarcinoma

Trial in progress: RASolute 302—A phase 3, multicenter, global, open-label, randomized study of daraxonrasib (RMC-6236), a RAS(ON) multi-selective inhibitor, versus standard of care chemotherapy in patients with previously treated metastatic pancreatic ductal adenocarcinoma (PDAC). (ASCO 2025) - P3 | "Clinical Trial Registration Number: NCT06625320 The abstract will be released to the public on May 22, 2025 at 4:00 PM"

Clinical • Metastases • P3 data • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

Combinatorial screen with standard of care and selected anticancer agents identifies multiple combinations with activity against a panel of patient-derived colorectal organoids (AACR 2025) - "Following compound addition, organoid growth was measured by live bright field imaging every 24 h and cell viability was determined by CellTiter-Glo 3D at 48 h and 168 h. Modest responses were observed in most models from the combination of leucovorin with 5-FU; however, >1 log of cytotoxicity was observed in only several models. The panel was more responsive to FOLFOX, which was consistent with the sensitivity of models to oxaliplatin. Responses to TAS-102 varied and >1 log of cytotoxicity was observed in several models...Combination of the BCL-2/BCL-xL inhibitor pelcitoclax plus cobimetinib achieved >1 log of cytotoxicity in most organoid models. Combinations of cobimetinib with the EGFR inhibitors erlotinib, afatinib or cetuximab demonstrated synergy in many organoids according to the Bliss independence model and frequently achieved ≥1 log of cytotoxicity...The combination of cobimetinib and MRTX1133 had synergistic activity by Bliss independence in multiple..."

Clinical • Oncology • BCL2 • BCL2L1 • BRAF • KRAS • PIK3CA

AUM-302, A NOVEL TRIPLE PIM/PI3K/MTOR INHIBITOR, SYNERGIZES WITH KRAS INHIBITION AND IMPEDES THE GROWTH OF PANCREATIC DUCTAL ADENOCARCINOMA SPHEROIDS AND ORGANOIDS (DDW 2025) - "Single- and dual kinase inhibitors TP-3654, GDC-0941, and BEZ-235, and DMSO were used as controls...Finally, combinatorial assays revealed synergy between AUM-302 and the KRAS inhibitor RMC-6236 in reducing the growth of hT1 and hM1A organoids. By blocking kinase activity, AUM-302 demonstrates potent inhibitory activity in PDAC cell lines and organoids in two different 3D culture formats. Treatment with this novel triple PIM/PI3K/mTOR inhibitor may also sensitize PDAC to other therapies, such as KRAS inhibitors."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS

Revolution Medicines Announces First Patient Dosed in Phase 3 Clinical Trial Evaluating Daraxonrasib in Previously Treated Patients with RAS Mutant Non-Small Cell Lung Cancer (GlobeNewswire) - "Revolution Medicines, Inc...today announced the first patient has been dosed in RASolve 301, a global, randomized, open-label Phase 3 clinical trial. RASolve 301 will evaluate the safety and efficacy of daraxonrasib (RMC-6236), a RAS(ON) multi-selective inhibitor, in patients with previously treated, locally advanced or metastatic RAS mutant non-small cell lung cancer (NSCLC) compared to docetaxel chemotherapy....RASolve 301 is anticipated to enroll approximately 420 patients with NSCLC worldwide who have received one to two prior lines of therapy for the treatment of advanced disease including an anti-PD-1/anti-PD(L)-1 agent and platinum-based chemotherapy."

Trial status • Non Small Cell Lung Cancer

Combinations in NSCLC:…Daraxonrasib and pembrolizumab with or without chemotherapy (GlobeNewswire) - P1/2 | N=484 | NCT06162221 | Sponsor: Revolution Medicines, Inc. | "Today, the company shared data for ten patients in the 1L NSCLC setting treated with daraxonrasib and pembrolizumab, as of a February 10, 2025 data cutoff. No new safety signals were seen, and the overall safety profile was consistent with those of daraxonrasib alone and the standard of care agents. Hepatotoxicity did not appear as a safety signal (no Grade 3 or higher events) in the combination of daraxonrasib and pembrolizumab with or without chemotherapy....Daraxonrasib achieved a favorable MDI of 93% in combination with pembrolizumab and 90% with the addition of chemotherapy."

P1/2 data • Non Small Cell Lung Cancer

RAS(ON) inhibitor doublet of elironrasib with daraxonrasib in NSCLC (GlobeNewswire) - P1b | N=210 | NCT06128551 | Sponsor: Revolution Medicines, Inc. | "As of a February 10, 2025 data cutoff, in 33 patients treated with elironrasib at 200 mg BID and daraxonrasib at doses ranging from 100 mg to 200 mg daily, Grade 3 TRAEs were reported in 46% of patients. There were no Grade 4 or 5 TRAEs. Hepatotoxicity was not observed as a safety signal (no Grade 3 or higher events) and QT prolongation was limited with one asymptomatic Grade 3 event (3%). The MDIs were favorable at 95% for elironrasib and 85% for daraxonrasib. The combination of elironrasib with daraxonrasib showed encouraging preliminary antitumor activity in patients with NSCLC who have been previously treated with a KRAS G12C(OFF) inhibitor. The ORR was 62% and the DCR was 92%."

P1 data • Non Small Cell Lung Cancer

Advance daraxonrasib into first-line metastatic and earlier-line randomized pivotal trials in patients with PDAC (GlobeNewswire) - "Planning continues for registrational trials for daraxonrasib as first-line (1L) treatment for patients with metastatic PDAC and as adjuvant treatment for patients with resectable disease, and the company expects to initiate both studies in the second half of this year."

New trial • Pancreatic Ductal Adenocarcinoma

Execute pivotal trials with daraxonrasib monotherapy in patients with previously treated metastatic pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC) (GlobeNewswire) - "In RASolute 302, a global Phase 3 trial in patients with previously treated PDAC, the company continues its strong pace of enrollment in the U.S. and has begun enrolling patients in the EU and Japan. The company expects to substantially complete enrollment this year to enable an expected data readout in 2026. For RASolve 301, a global Phase 3 trial in patients with previously treated NSCLC, the company is currently activating study sites."

P3 data • Trial status • Non Small Cell Lung Cancer • Pancreatic Ductal Adenocarcinoma

Evaluating the efficacy of RAS(ON) inhibitor RMC-6236 combined with chemotherapy and other targeted therapies in 3D models involving patients with KRAS-mutated pancreatic cancer (AACR 2025) - "Synergy studies explored combinations of RMC-6236 with gemcitabine and abraxane chemotherapies, along with other targeted therapies, including CDK7, WNT, and mTOR pathway inhibitors. The combination of RMC-6236 with standard chemotherapy and targeted therapies enhances its antitumor activity, suggesting a promising strategy for improving therapeutic outcomes in pancreatic cancer. The observed synergistic interactions, especially with WNTi, warrant further investigation in clinical trials to evaluate the potential of this combination approach in improving treatment responses."

Clinical • Oncology • Pancreatic Cancer • Solid Tumor • CAFs • KRAS

The efficacy of NST-628, a non-degrading pan-RAF/MEK molecular glue, and MEK inhibitors for overcoming acquired osimertinib resistance mediated by TRIM24-BRAF fusions in EGFR mutant NSCLC (AACR 2025) - "Next, we utilized a panel of compounds targeting the RAS/RAF/MAPK pathway including agents targeting pan-RAS (RMC-6236 and RMC-7977), SHP2 (RMC-4550), BRAF (dabrafenib, encorafenib, tovorafenib and vemurafenib), pan-RAF (TAK-632), MEK (binimetinib, cobimetinib, selumetinib and trametinib), pan-RAF/MEK (NST-628) and assessed whether targeting signal transduction molecule downstream of EGFR could overcome this adaptative resistance mechanism. TRIM24-BRAF expressing cells showed minimal sensitivity to BRAF, SHP2 or RAS targeting single agents. Taken together, our findings indicate that expression of TRIM24-BRAF fusion induce osimertinib resistance in EGFR mutant NSCLC and targeting the MEK pathway using trametinib or NST-628 can overcome osimertinib resistance in this setting."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • EGFR • TRIM24

Drug combination inhibits genes that drive aggressive pancreatic cancer, study finds (Medical Xpress) - "Study findings indicate that a newly discovered drug, RMC-6236, also known as Daraxonrasib, is a powerful inhibitor of RAS (including KRAS, NRAS and HRAS). These are commonly mutated cancer-causing genes that drive the formation of many types of tumors, including pancreatic cancer. This study evaluated the effectiveness of RMC-6236 in patient-derived pancreatic tumors harboring KRAS mutations....According to this initial study to emerge from the Research Institute's new Center for Translational Science laboratory, RMC-6236, when combined with other proven pancreatic cancer drugs, is a promising new agent against RAS, particularly KRASG12X."

Preclinical • Pancreatic Cancer

Oral and selective ribonucleotide reductase (RNR) inhibitor, BBI-825, suppresses acquired resistance to mutant-specific, pan, and multi-RAS targeting inhibitors (AACR 2025) - P1 | "In this preclinical study, we sought to understand whether BBI-825 broadly antagonizes acquired resistance to mutant-specific, pan, and multi-RAS inhibitors in a range of tumor models.We tested the ability of BBI-825 to prevent or delay development of acquired resistance to RAS targeting in a panel of KRASG12D/C/V driven tumor cell lines when used in combination with mutant specific KRASG12D (MRTX-1133, RMC-9805), KRASG12C (adagrasib, sotorasib), pan-KRAS (BI-2493), and multi-RAS (RMC-6236) inhibitors. Overall, we found that BBI-825 successfully antagonizes the development of acquired resistance to mutant-specific, pan, and multi-RAS inhibitors in a range of preclinical models. These findings support clinical investigation of BBI-825 in combination with mutant-specific, pan, and multi-RAS inhibitors to prevent or delay resistance and prolong duration of response."

Preclinical • Oncology • Solid Tumor • KRAS

Integrative analysis of acquired drug resistance to KRAS(G12D) inhibitors (AACR 2025) - "Novel therapeutic approaches such as RAS(ON) inhibitors like RMC-6236 or specific KRAS(G12D) PROTAC degraders can significantly inhibit cell proliferation in vitro not only in MRTX1133 acquired resistance but also in adagrasib resistance models. Complex transcriptomic reorganization shows the upregulation of CD24 -a potential cancer stem cell related gene- and the epithelial to mesenchymal signature highlight the difficulty to target drug resistant cells. These findings emphasize the necessity to design combinatorial treatments to prevent and delay the acquisition of drug resistance in KRAS-driven cancers."

Colorectal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • AVEN • CD24 • HRAS • KRAS • NRAS

RCZY-690 and RCZY-680: Novel, highly potent, and orally bioavailable, tri-complex pan RAS-MULTI(ON) inhibitors with distinctive oral pharmacokinetic profiles, exhibiting broad anti-tumor activities in CDX models (AACR 2025) - "Although KRAS G12C inhibitors like sotorasib and adagrasib show promise for NSCLC, resistance develops rapidly, and effective therapies are still lacking for over 85% of RAS-driven or RAS-amplified cancers.Herein, we report RCZY-690 and RCZY-680 as novel and potent tri-complex RAS-MULTI(ON) inhibitors...This approach, exemplified by the lead compound RMC-6236, has shown promise in KRAS-mutant PDAC and NSCLC patients in phase 1 study...The superior anti-tumor efficacy may be attributed to their highly potent cellular cytotoxicity, long mouse half-lives (10.1 h and 4.8 h, respectively), and high oral exposure levels. In conclusion, RCZY-690 and RCZY-680 are tri-complex pan RAS-MULTI(ON) inhibitors with best-in-class clinical potential for treating RAS-driven solid tumors."

PK/PD data • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BRAF • DUSP6 • HRAS • KRAS • NRAS

A 1st in class pan-RAS inhibitor with robust antitumor activity in PDAC models and advantages over other RAS inhibitors to escape resistance (AACR 2025) - "Growth assays involving direct comparison of ADT-007 with mutant-specific KRASG12C inhibitors (sotorasib), pan-KRAS inhibitors (BI-2865), or other pan-RAS inhibitors (RMC-6236) revealed more complete cancer cell killing by ADT-007. Finally, cancer cell lines resistant to KRASG12C and KRASG12D inhibitors retained complete sensitivity to ADT-007 but showed resistance to MRTX849 and MRTX1133, respectively. These results show the unique advantages of ADT-1004 over mutant-specific KRAS, pan-KRAS, and other pan-RAS inhibitors to escape resistance that limits the efficacy of RAS inhibitors FDA-approved or in clinical trials."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • BRAF • EGF • 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

Targeting FAK by Ifebemtinib synergizes with Pan RAS inhibitors in treating RAS mutant cancers (AACR 2025) - "Co-administration of a clinical-stage FAK inhibitor, Ifebemtinib (also known as Ifebe, IN10018), with RMC6236, a Pan-RAS inhibitor, exhibited synergistic cytotoxic effects in multiple RAS-mutant cancer cell lines. In summary, our study reveals that the combination of FAK inhibitor Ifebe with Pan-RAS inhibitor exhibits synergistic anti-cancer effects and further improves the outcomes of PD-1 blockade therapy. These preclinical results support the need for further clinical investigation."

IO biomarker • Oncology • KRAS • NRAS

Mechanisms of resistance to RAS-GTP inhibition in pancreatic cancer (AACR 2025) - "A related compound, RMC-6236, is under clinical investigation for both RAS-mutant solid tumors and metastatic PDAC. Targeting these kinases in combination with RMC-7977 reverted resistance in models of innate and acquired resistance, suggesting a potential approach to investigate preventing or overcoming resistance in patients. Collectively, our pre-clinical data suggest that resistance to RAS inhibition with RMC-7977 may arise via multiple mechanisms, among them secondary RAS mutations, PI3K pathway-activating mutations, or cell-state changes that drive adaptive signaling through ECM-signaling pathways."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

Targeting KEAP1/NRF2 signaling sensitizes KRAS-driven NSCLC to KRAS inhibitors (AACR 2025) - "The results demonstrated that silencing NRF2 could significantly improve the responsiveness of both the pan-KRAS inhibitor RMC-6236 and the KRAS G12C inhibitor Sotorasib in A549 and H2122 cells. Taken together, our study demonstrates that knockdown of NRF2 can enhance the effectiveness of KRAS inhibitors in treating NSCLC patients with KEAP1 mutations. This finding provides the scientific foundation for developing combination therapy strategies that target both NRF2 and KRAS to improve patient outcomes."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AKR1B10 • AKR1C1 • KRAS • STK11

Adaptive rewiring after prolonged KRAS inhibition sensitizes PDAC cells to sequential targeting with ferroptosis inducers (AACR 2025) - "A drug screen on primary PDAC cell lines derived from the model that were resistant to KRASG12D inhibition identified a strong RSL3-induced ferroptosis sensitivity of KrasG12D-depleted cell lines compared to their KrasG12D-proficient counterpart. Inhibitors MRTX1133 and RMC-6236 also conferred ferroptosis sensitization in various mouse and human PDAC cell lines...These, together with global changes in transcriptome, suggest that multiple pathways likely contribute to ferroptosis sensitization, including KEAP-NRF2 redox balance pathway, iron and lipid metabolism, and also hint at involvement of TGFβ-EMT signaling axis. Our results suggest that a sequential two-hit therapeutic approach with KRAS inhibition followed by subsequent ferroptosis induction could efficiently mitigate resistance to KRAS-inhibitor based therapies in PDAC."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KEAP1 • KRAS • MAP3K7 • SLC7A11

Targeting KRAS in appendiceal cancer: promising results with MRTX1133 and RMC-6236 in organoids and PDX models (AACR 2025) - "Single-agent MRTX1133 was highly potent and specific to KRASG12D AA tumors, whereas pan-RAS inhibitor RMC-6236 inhibited both KRASG12D and KRASG12V organoids at nanomolar concentrations. MRTX1133 demonstrated robust suppression of the RAS-MEK-ERK pathway and prolonged survival in vivo models of AA."

Appendix Cancer • Oncology • CASP3 • CASP7 • 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

Determination of the MYC- and TEAD-dependent transcriptome in pancreatic cancer (AACR 2025) - "We recently reported MYC amplification and TEAD-dependent transcriptional activation by YAP as drivers of resistance to the multi-RAS inhibitor RMC-7977 (RASmulti), the preclinical analog of RMC-6236...To determine the TEAD-dependent transcriptome, we treated a panel of three sets of paired naïve and RASmulti-resistant KPC cell lines, derived from an autochthonous mouse model of PDAC, and of six human KRAS-mutant PDAC cell lines with the TEAD inhibitor IAG933, with RMC-7977, or with the combination...Proteomic profiling of PDAC cell lines with acquired resistance to RMC-7977 showed upregulation of TEAD-dependent gene products, supporting TEAD activation as a non-genetic mechanism of acquired resistance. Together, our findings expand the role of MYC and TEAD in supporting PDAC cell growth and resistance to RAS inhibition and provide rationale for further evaluation of combination therapeutic strategies to limit resistance."

Late-breaking abstract • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • KRAS • MYC

TNG462, an MTA-cooperative PRMT5 inhibitor, demonstrates strong efficacy in combination with clinically relevant targeted therapies in MTAP-null preclinical models (AACR 2025) - "This supports our clinical development plans for TNG462, which include targeted combinations with two RAS(ON) inhibitors, RMC-6236 and RMC-9805 from Revolution Medicines, as well as the EGFR inhibitor osimertinib from AstraZeneca...Significant efficacy was observed in preclinical models with the combination of TNG462 and CDK4/6 inhibitors, supporting a potential development path in GBM for our next generation CNS penetrant PRMT5 inhibitor, TNG456, with abemaciclib...However, TNG462 monotherapy at a clinically relevant dose achieved comparable benefits to the combination. Collectively, these findings strongly support evaluating TNG462 in combination with other targeted therapies in clinical trials for patients with cancers that exhibit MTAP loss."

Combination therapy • Preclinical • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CDKN2A • KRAS • MAT2A • MTAP